ABSTRACT: Breathing instability during sleep, which is a hallmark of sleep apnea, is characterized by recurring cycles of apnea followed by hyperpnea. These recurring cycles lead to intermittent hypoxia (IH) and excessive arousal from sleep, which may result in a number of pathophysiological conditions including daytime sleepiness and hypertension. In recent years, the role of an endogenous circadian rhythm in modulating the severity of many disorders has become evident. Accordingly, the severity of sleep apnea may be modulated in part by a circadian timing system, principally through the modification of mechanisms that impact on breathing stability. These modifications might include alterations in chemoreflex properties (i.e. sensitivity or threshold of response) or control of upper airway muscle activity. Thus, the overlying objective of this proposal is to determine if an endogenous circadian rhythm modulates mechanisms, directly or indirectly via the expression of respiratory plasticity (long-term facilitation of minute ventilation and upper airway muscle), which ultimately improves breathing stability during sleep at specific points within a 24 hour day/night cycle. Aim 1 of our proposal will establish if breathing instability is reduced during daytime compared to nighttime sleep. This aim will also test the hypothesis that increased stability is associated with reduced chemoreflex sensitivity to carbon dioxide, an increased carbon dioxide reserve and enhanced neuromuscular control of upper airway muscles (i.e. mechanisms that impact on breathing stability) during sleep in the daytime compared to the nighttime. Aim 2 of our proposal will establish if forms of respiratory plasticity that promote breathing stability (i.e. ventilatory lon-term facilitation and long-term facilitation of upper airway muscle activity) are enhanced in the day compared to the night. Likewise, this aim will establish if enhancement of these forms of plasticity leads to an improvement in breathing stability that exceeds measures obtained before exposure to intermittent hypoxia. Aim 3 is designed to determine whether or not the therapeutic pressure required for the elimination of breathing events in individuals with sleep apnea will be less in the afternoon or evening compared to the early morning in accordance with circadian modulation of mechanisms that impact breathing stability. Likewise, this aim will determine if the therapeutic pressure required to eliminate apnea at a given time of day is less after the initiatio of respiratory plasticity following exposure to IH or sustained mild hypercapnia. If mechanisms and forms of respiratory plasticity that impact on breathing stability are modulated by a circadian rhythm this will ultimately impact on the treatment of sleep apnea. Patients could derive benefit from scheduling naps at times when breathing is most stable. Likewise, therapeutic pressures required to treat apnea would be less under conditions of increased breathing stability which could improve treatment compliance. Moreover, novel adjunct therapies such as intermittent hypoxia administered in combination with continuous positive airway pressure (i.e. a well-established treatment for sleep apnea) could result in reduced therapeutic pressures particularly if treatment was administered at times when the magnitude of respiratory plasticity and breathing stability were at their peak.